Liraglutide 204656-20-2
Liraglutide (NN2211), marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U. S. Food and Drug Administration (FDA) on January 25, 2010. Liraglutide is marketed under the brandname Victoza in the U. S. and Europe. It has been launched in Germany, Denmark, the Netherlands, the United Kingdom, Ireland, and the United States. Phase I trials of an oral variant of Victoza (NN9924) are starting in 2010.
Cancer concerns
On April 2, 2009, an FDA advisory panel reviewed the significance of malignant C-cell carcinoma and thyroid C-cell focal hyperplasia in rats and mice. Some say the tumors were caused by a non-genotoxic, specific receptor-mediated mechanism to which rodents are particularly sensitive whereas non-human primates and humans are not. The Victoza label carries a Black Box Warning, "Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk". The FDA said that serum calcitonin, a biomarker of medulliary thyroid cancer, was slightly increased in liraglutide patients but still within normal ranges, and it required ongoing monitoring for 15 years in a cancer registry.
Pharmacodynamics
Studies to date suggest liraglutide improves control of blood glucose. It reduces meal-related hyperglycemia (for 12 hours after administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion. Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying. GLP-1(7-37) has a half-life of 1. 5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP. (reference-www. drugs. com)Liraglutide may have advantages over current therapies:*It acts in a glucose-dependent manner, meaning that it will stimulate insulin secretion only when blood glucose levels are higher than normal. Consequently, it shows negligible risk of hypoglycemia. *It has the potential for inhibiting apoptosis and stimulating regeneration of beta cells (seen in animal studies). *It decreases appetite and maintains body weight, as shown in a head-to-head study versus glimepiride. *It lowers blood triglyceride levels. *It has only mild and transient side effects, mainly gastrointestinal.
Pharmacokinetics
Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. GLP-1, in its natural form, is short-lived in the body (the half-life after subcutaneous injection is approximately one hour), so it is not very useful as a therapeutic agent. However, liraglutide has a half-life after subcutaneous injection of 11–15 hours, making it suitable for once-daily dosing(less frequent than the currently approved Byetta form of exenatide, which is twice daily, but considerably more frequent than the once weekly Bydureon form of exenatide that is scheduled for a decision from the FDA regarding marketing approval by early March 2010). The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at one position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Binding with albumin also results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1.
| Systematic (IUPAC) name: | L-histidyl-L-alanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-N6-[N-(1-oxohexadecyl)-L-γ-glutamyl]-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-glycine |
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| Liraglutide CAS number: | 204656-20-2 |
| ATC code: | A10BX07 |
| PubChem: | |
| DrugBank: | |
| Formula: | C172H265N43O51 |
| Molecular mass: | 3751.20 g/mol |
| Liraglutide Assay/Purity: | Typically NLT 98% |
